Rett Syndrome (RTT) is an X-linked progressive neurodevelopmental disorder and is a common cause of severe intellectual disability and autistic-like symptoms in girls. Mutations in MECP2, a methyl-CpG-binding protein, cause of the majority of RTT cases. MeCP2 is a methyl-CpG-binding protein that represses transcription by binding the NCoR/HDAC3 histone deacetylase complex. Mutation of arginine 306 to cytosine (R306C) causes RTT and disrupts binding of MeCP2 to the NCoR complex, suggesting that MeCP2-NCoR interaction is critical for brain development and that disrupting this complex leads to RTT. The Greenberg laboratory, in its studies of neuronal activity-dependent gene transcription, discovered that in response to sensory experience MeCP2 becomes phosphorylated at threonine 308 (T308) and that this phosphorylation event perturbs the interaction of NCoR with MeCP2. Furthermore, preliminary experiments suggest that mutation of MeCP2 T308 to alanine (T308A) leads to attenuation of the induction of the activity-regulated gene Npas4. The Npas4 gene encodes a transcription factor that controls inhibitory synapse formation onto excitatory neurons. Thus, our preliminary data suggest that the interaction between MeCP2 and NCoR may be critical for Npas4 expression and is misregulated in RTT. To test this hypothesis we propose the following specific aims: (1) to further investigate if MeCP2-NCoR complex regulates neuronal activity-dependent gene expression and (2) to determine if the MeCP2-NCoR complex regulates gene expression by associating with the regulatory region of the Npas4 gene in an activity-dependent manner. It is our hope that these proposed experiments will provide a better understanding of MeCP2 function and will suggest potential therapeutic strategies for treating RTT.